1. Field of the Invention
This invention relates to the fields of cell biology, medicine and cancer. More specifically, this invention is related to the control of cell proliferation through antisense technology.
2. Description of the Related Art
Peptide growth factors are key regulators of normal and cancer cell proliferation and differentiation (Salomon et al. (1995) Crit. Rev. Oncol. Hematol. 19:183-232). Growth factors of the epidermal growth factor (EGF) gene family, such as transforming growth factor α (TGFα), act as autocrine and paracrine mitogens for human epithelial cancers including breast, colon, ovary, kidney, prostate and lung (Salomon et al. (1995) Crit. Rev. Oncol. Hematol. 19:183-232). TGFα binds to the extracellular domain of the epidermal growth factor receptor (EGFR) and activates its intracellular tyrosine kinase domain (Salomon et al. (1995) Crit. Rev. Oncol. Hematol. 19:183-232). Enhanced expression of TGFα and/or EGFR has been detected in the majority of human carcinomas and is associated with poor prognosis (Salomon et al. (1995) Crit. Rev. Oncol. Hematol 19:183-232). Therefore, the TGFα-EGFR autocrine pathway has been proposed as a therapeutic target (Mendelsohn (1997) J. Natl. Cancer Inst. 89:341-343; Mendelsohn (1997) Clin. Cancer Res. 3:2703-2707).
Different pharmacologic and biologic approaches have been developed for blocking EGFR activation and/or function in cancer cells. For example, various anti-EGFR blocking monoclonal antibodies (MAb), recombinant proteins containing TGFα or EGF fused to toxins, and EGFR tyrosine kinase inhibitors have been generated and characterized for their biologic and potentially therapeutic properties (Fan et al. (1998) Curr. Opin. Oncol. 10:67-73). MAb C225, a chimeric human-mouse IgG1 MAb, is in phases II-III clinical trials in cancer patients (Fan et al., supra). Compounds that selectively block the ligand-induced activation of the EGFR tyrosine kinase (EGFR tyrosine kinase inhibitors, such as ZD1839) (Ciardiello et al., (2000) Clin. Cancer Res. 6(5):2053-2063 are also currently under clinical evaluation in cancer patients (Noonberg (2000) Drugs 59:753-67). Previous studies have demonstrated that agents such as MAb C225 interfere with EGFR activation, potentiate the antitumor activity of cytotoxic drugs, including platinum-derivatives, taxanes, topoisomerase I and II inhibitors (Mendelsohn (1997) J. Natl. Cancer Inst. 89:341-343; Mendelsohn (1997) Clin. Cancer Res. 3:2703-2707; Ciardiello et al. (1999) Clin. Cancer Res. 5:909-916) or EGFR tyrosine kinase inhibitors (Ciardiello et al. (2000) supra).
Unfortunately, none of these approaches have yet emerged as an effective therapeutic. There is, therefore, a need for new approaches to blocking EGFR activity in cancer cells.